This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The HER-2/neu oncoprotein is a member of the epidermal growth factor receptor family and is overexpressed in about 25% of invasive breast cancers, and is associated with a worse prognosis. Curiously, however, 75% of non-invasive breast cancers (ductal carcinoma in situ or DCIS) overexpress the same protein, and these patients are at a greater risk of tumor relapse or progression to invasive carcinomas (38%) compared to those with HER-2/neu negative DCIS. Some patients with HER-2/neu positive cancers have pre-existing immunity against this antigen. It has also been shown in our laboratory, using a transgenic mouse model of HER-2-positive breast cancer that certain types of immune responses, rather than destroying the tumor target, cause loss of the HER-2 antigen (known as "immunoediting"), which results in recurrence of the cancer, which then does not express HER-2/neu. In particular, interferon-gamma (IFN- secreting T cells and production of certain classes of antibody are associated with this phenomenon. It may be that IFN- receptors, which are expressed by breast cancer cells, mediate this immunoediting effect. Similarly, patients with advanced HER-2/neu positive breast cancers who were treated with a monoclonal IgG antibody (Trastuzumab, which binds to region IV of the extracellular domain [ECD] of HER-2/neu) developed resistance within a year of treatment, sometimes associated with the loss of HER-2/neu in their tumor. On the other hand, Pertuzumab, which binds to region II of the ECD and disrupts homo- and hetero-dimerization dependent HER-2/neu signaling, induced cancer cell apoptosis with no evidence of inducing HER-2/neu loss. Based on these data and findings in our laboratory, we hypothesize that specific types of immune responses against HER-2/neu (particularly IFN- production by T lymphocytes and/or production of IgG antibody against ECD region IV) encourages HER-2/neu antigen loss and "escape" of cancers from immune attack. This would lead to progression from HER-2/neu positive DCIS to HER-2/neu negative invasive breast cancer, which would be consistent with high proportion of expression in the early lesions and the much lower proportion of patients with HER-2 overexpressing invasive cancers. Conversely, we predict that T lymphocyte production of granzyme B and/or IgG antibody responses against ECD region II would lead to tumor cell destruction without loss of the target antigen, and thus a lower likelihood of progression or relapse. By studying immune responses in women with HER-2/neu positive or negative DCIS and invasive breast cancer, as well as examining breast cancers for expression of IFN- receptors, we hope to confirm these hypotheses.